In the manufacturing of biopharmaceuticals using cell culture processes, one problem has been that proteins in the cell culture can form aggregates. The aggregates are usually formed by more than one molecule, or contain partially or completely denatured molecules. Aggregates are not usually removed in filtering or other preliminary purification processes because of their similarity to the biopharmaceutical product.
Aggregates can be a problem in biopharmaceutical manufacture. The aggregate level of the starting bulk must be kept below 0.1% in order to formulate high strength biopharmaceutical products, i.e., greater than 100 mg/ml, with an acceptably low aggregate concentration. Therefore, elimination of aggregates from the bulk product in an efficient manner is needed for successful production of high strength biopharmaceuticals.
A conventional method to remove aggregates from biological solution is by gel filtration, which is based on the molecular size difference between aggregates and product molecules. However, this method is difficult and costly for large scale production and when one wishes to concurrently remove other impurities, including endotoxins and nucleic acids, for production of high strength pharmaceuticals.